There has been a worldwide increase in the number of infections caused by Gram-negative bacteria. The resistant Gram-negative bacteria has been a serious global health concern as is evident from U.S. Centers for Disease Control and Prevention (CDC) report on Antibiotic Resistant Threats in the United States, 2013.
Gram-negative bacteria are common causes of intra-abdominal infections (IAIs), urinary tract infections (UTIs), nosocomial pneumonia, and bacteremia. Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa are important pathogens accounting for 27% of all pathogens and 70% of all Gram-negative pathogens causing healthcare-associated infections (Sievert D M, et al., Infect Control Hosp Epidemiol. 2013; 34:1-14). P. aeruginosa is the most common Gram-negative cause of nosocomial pneumonia and the second most common cause of catheter-related UTIs and E. coli is the most common cause of UTIs (Sievert D M, et al., Infect Control Hosp Epidemiol, 2013; 34:1-14). Cases of UTI caused by extended spectrum beta lactamase (ESBL)-producing E. coli and K. pneumonia as well as P. aeruginosa, including multidrug-resistant (MDR) strains are increasing (Zilberberg M D, et al., Infect Control Hosp Epidemiol. 2013; 34:940-946).
Treatment options for infections caused by Gram-negative bacteria and resistant bacteria thereof are very limited. Therefore, there is a serious need for a new antibiotic having a novel mechanism of action to meet the needs of the patients.
As such benzoxaborole compounds have been known which inhibit leucyl-tRNA synthetase (LRS enzyme), for example WO 2012/33858, WO 2011/60199, WO 2011/49971, WO 2011/037731, WO 2010/080558, WO 2009/140309, WO 2008/157726 and WO 2008/70257. The PCT publication WO 2013/154759 provides a combination of an amino acid or amino acid salt that is capable of being acylated onto tRNAleu by LRS and a benzoxaborole compound.
Other references disclosing benzoxaborole as a structural moiety includes WO2014/173880, WO2014/149793, WO2014/121124, WO2014/07831, WO2013/78070, WO 2011/094450, WO 2011/063293, WO 2011/022337, WO 2011/019616, WO 2011/019612, WO 2011/19618, WO 2011017125, WO 2010/45503, WO 2010/45505, WO 2010/027975, WO 2010/028005, WO 2009/111676, WO 2007/146965, WO 2007/131072, WO 2007/095638, WO 2007/78340, WO 2006/089067 and WO 2005/013892.
However, none of the cited references disclose tricyclic benzoxaborole compounds, provided in the present invention, as antibacterial agents targeting Gram-negative bacteria and resistant bacteria thereof for the treatment and/or prevention of bacterial infections, for example intra-abdominal infections (IAIs), complicated urinary tract infections (cUTIs), nosocomial pneumonia or bacteremia.
WO2015/21396, WO2015/16558 and WO2013/93615 disclose tricyclic boron compounds. None of the aforementioned specifically contemplates any compound provided in the present invention.
GSK2251052 (benzoxaborole compound) is the first antibacterial investigational drug of this class, as reported, for example, by Zane et al., in a poster Safety, tolerability, and pharmacokinetics of a novel Gram-negative antimicrobial, in healthy subjects, 21st European Congress of Clinical Microbiology and Infectious Diseases, 2011, Milan, Italy. The clinical development of GSK2251052 (or AN3365) has been discontinued due to the identification of microbiological findings of resistance in the Phase 2b trial for the treatment of complicated urinary tract infections (O'Dwyer K, et. al Antimicrob Agents Chemother. 2015; 59(1):289-98). It has been considered that such benzoxaborole compounds are not suitable for applying to clinical settings.
However, compounds of the present invention have been found to be suitable for applying in clinical settings. They have much improved profile over AN3365, for example 1) in terms of resistance on treatment, 2) no significant shift in MICs in Pseudomonas efflux deleted and over-expression strains, 3) retains activity in human urine, 4) lacks putative site of metabolism and is stable in human S9. Pseudomonas has strong efflux mechanism that is responsible for resistance to existing drugs. Compounds of the present invention works on such efflux over-expressing clinical isolates. In addition, compounds of the present invention were found to be safe and efficacious.
Thus, the present invention provides a great hope for a new antibiotic to meet the challenges of a serious global health concern due to Gram-negative bacteria and resistant bacteria thereof causing bacterial infections including, but not limited to, intra-abdominal infections (IAIs), complicated urinary tract infections (cUTIs) or nosocomial pneumonia.